Paradigm Shift in Comparability Assessment:

Transcription

1 Paradigm Shift in Comparability Assessment: How Quality by Design (QbD) and Process Analytical Technology (PAT) can improve Structure-Activity Relationship (SAR) evaluation and its relevance to comparability protocols and biosimilars Robert L. Zeid Principal Consultant TLI Development 113 SE 5 th St. Oak Island, NC (910) robert_zeid@msn.com 1

2 Overview Key Concepts Biologics development is complicated. An enormous number of variables influence product quality and process consistency. This has evolved into the product = process paradigm with highly regulated change control for post-approval manufacturing changes. No matter how controlled the manufacturing process may be, without using the central tenets of Quality by Design (QbD) and Process Analytical Technology (PAT) linked to structure- activity-relationships (SAR) of the active ingredient - one is limited to empirical assumptions about the impact of a proposed change on safety or efficacy. By using QbD and PAT in the development programs for API and finished product, and linking those SAR changes to their impact on nonclinical and clinical programs, one can create enormous process and regulatory flexibility. Comparability protocols can be significantly improved by this approach. By using forced degraded samples of innovator and comparator product in the orthogonal analytical systems, this can also aid in the e development of biosimilars and biologics monographs. 2

3 Quality by Design (QbD) Key Concepts of Quality by Design (QbD) Integrating prior knowledge and pharmaceutical development into CMC programs is based on three tenets: We know what is important. Product and process characteristics are defined by a combination of prior knowledge and assumptions ; confirmed by experimental assessment during product development We have established a framework of relationships and impact for each of these quality parameters. A multivariate model links product & process measurements to desired attributes; defining an edge of failure for product quality and process parameters. We can measure the combined impact on safety and efficacy. Clinical testing is viewed as confirmatory performance of the predictive model. Creating process and regulatory flexibility by design space The product and process performance characteristics are scientifically designed to meet specific objectives, not merely empirically derived from performance of test batches An ability to define and defend particular product quality attributes or process parameters and their potential impact on safety and efficacy 3

4 Process Analytical Technology (PAT) Key Concepts of Process Analytical Technology (PAT) Scientific, risk-based framework intended to support innovation and efficiency in pharmaceutical development, manufacturing, & quality assurance: A system for designing, analyzing, and controlling manufacturing Shifting process evaluation away from product testing and towards real, in-time measures Identifying and measuring critical quality and performance attributes Quality is built into the product through a comprehensive understanding of: The intended therapeutic objectives, patient population, route of administration, and pharmacological, toxicological, and pharmacokinetic characteristics The chemical, physical, and biopharmaceutical characteristics of the drug Design of a product and selection of product components and packaging based on the criteria above Design of manufacturing processes using principals of engineering, material science, and quality assurance to show acceptable and reproducible product quality over the shelf life 4

5 Active Pharmaceutical Ingredient (API) Programs How do you go about implementing QbD and PAT for a program? The first step is to identify the subcomponents of major areas and the variables. The major tasks for an API program include 5

6 Finished Product Programs The major aspects of the finished product program are comprised of 6

7 Nonclinical Programs The major aspects of the nonclinical program are comprised of 7

8 Clinical Programs The major aspects of the clinical program are comprised of 8

9 Process Development Programs The major aspects of the process development program are comprised of 9

10 Comparability is imperative to an integrated development program Changes in these programs over the development time line must be minimized by comparability assessments. 10

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13 Determination of Critical Parameters Design of Engineering (DOE) Studies: Hi/lo experiments Spiking with impurities Extended process parameters Outcome is usually determine on purity and yield Further confirmatory studies with formulation of API into finished product and stability studies for both Principle Component Analysis: Multiple variables assessed in a matrix Statistical Process Control (SPC) Trending of established processes Forced Degradation Studies Correlation of physico-chemical profiles in biological systems 13

14 Statistical Process Control (SPC) Trending of established processes: Value is showing process performance Can be used to help address corrective actions May be used to justify lot release for some process parameters exceeding validation limits when it can be shown the (1) reason for excursion was identified and corrected and (2) the impact on product quality was not significant Limits of this approach is that without correlation to SAR, the nature of some changes cannot be fully understood. Some in vitro and in vivo assays may not be sensitive enough to detect subtle changes in physico-chemical profiles 14

15 Structure-Activity Relationships (SAR): Mining SAR for its impact on other product quality attributes 15

16 Defining SAR thru Forced Degradation: Evaluating the Sensitivity of Assay Methods Evaluate SAR by a parallel assessment of biological activity and physico-chemical profile: What is sensitivity of biological assay to detecting loss of potency? What is variability of potency assay and how many samples must be run to establish statistical confidence? What is rate of impurity formation under various stability conditions? Does a rise in impurities correlate with loss of biological activity? Is it possible to establish a threshold of impurity formation and/or other physicochemical profiles with a loss in potency? What key features are affected? Can the combined data be used to establish QbD and critical process parameters? 16

17 Formulating SAR into a QbD/PAT Matrix Matrix is broken out by stage, process steps, parameters, and impact on product Data supporting these evaluations should be cross-referenced in a database or data management system for easy retrieval and review If impacted material was evaluated in a bioassay/potency method, nonclinical study, or surrogate endpoint study, those data should be confirmed for characteristics consistent against other batches. How does the profile of a failed batch compare to a passing one? 17

18 Some changes may be too significant to be addressed solely through SAR Significant manufacturing changes will require a tiered testing approach as basis of comparability assessment Physico-Chemical Characterization of pre- and post-change material: Methods and assays must be sensitive enough to detect deamidated, oxidized, cleaved, and aggregated forms, Post-translational modification testing such as glycosylation, sulfation, phosphorylation, or formylation should also be compared to trended profiles of passing batches Vaccines should have comparable affinity from the same donor serum showing no difference in binding Bioassays & Animal Models Disease models need to be assessed for sensitivity of detecting failed material ADME and Toxicokinetics can help show comparability for PK and PD Human Studies PK/PD Studies: Where the pharmacokinetic (PK) action is much less than the pharmacodynamic (PD) activity such as vaccines and immune modifying agents the human PK/PD study will need to be longer to assess the full range of PD effects and include more thorough safety analysis Immunogenicity: This needs to be assessed in post-approval changes as part of the Risk Evaluation Management System (REMS). 18

19 Comparable, Therapeutically Equivalent, and Biosimilar How might a QbD and PAT approach be useful in judging impact by SAR? 19

20 Well characterized proteins allow detailed knowledge of mechanism of action and impact of SAR on potency Insulin Human Growth Hormone 20

21 Creation of Biologics Monographs: Expanding knowledge of SAR beyond simple proteins will allow integration into compendial monographs for use by regulatory authorities. 21

22 Summary of Key Points Process design requires integrated approach of SAR, protein expression systems, and characterization testing all linked to bioassay and manufacturing parameters. Scale of manufacture will change depending on process development data and clinical/market needs. Try to arrange significant changes prior to Phase III to avoid costly delays in comparability studies. Process development can be optimized via PCA and linked to SAR. Comparability studies will be vital to supporting consistency across manufacturing and process development changes. Manufacturing controls must reflect product parameters well within edge of failure Stability data must be supported by extensive characterization testing to show subtle changes do not impact purity, potency, or safety The QbD and PAT approach using SAR can be the next step in process design space for biologics and open the door for improved biosimilars and compendial monographs of biologics. 22

23 Conclusion Using this approach will not replace the necessity of conducting confirmatory clinical studies for significant manufacturing changes but it should improve the confidence of the comparability protocols being approved, of which > 97% of them are approved without requiring clinical data. With respect to biosimilars, a side-by side comparison of the sensitivity of these methods to innovator material should provide a thorough correlation of physicochemical profiles to bioassay activity and clinical responses. With these data in hand, the regulatory authorities will have a better sense of what differences are clinically relevant versus those that are not as is currently done with today s comparability exercises. Finally, the ability to integrate these findings into compendial monographs should allow for a harmonized approach to regulators with respect to critical SAR attributes that must be conserved in development for safety and efficacy. 23